Appetite-stimulating agents and remedies for anorexia

ABSTRACT

An appetite-stimulating agent and a therapeutic agent for anorexia, each comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the following general formula (I):  
                 
 
     wherein the ring A represents a monocyclic or bicyclic aromatic ring which may be substituted,  
     the ring B represents a 6-membered unsaturated hydrocarbon ring or a 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, each of which may be substituted,  
     the ring C represents a 5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted,  
     W represents a single bond or —CH═CH—,  
     X represents —N(R′)— or an oxygen atom,  
     Y represents a carbon atom or a nitrogen atom,  
     Z represents —N(R 2 )- or a nitrogen atom, and  
     R 1  and R 2  may be identical or different and each represents a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, or a hydrate thereof.

TECHNICAL FIELD

[0001] The present invention relates to an appetite-stimulating agent.The present invention also relates to a therapeutic agent for anorexia,and more particularly to therapeutic agents for anorexia nervosa,apocleisis emaciation, and anorexia and emaciation accompanyingcancerous cachexia.

BACKGROUND ART

[0002] Appetite and eating behavior are controlled by a networkmechanism in which various regulator groups are complexly linked withone another, thereby maintaining a constant internal environment andbody weight. However, in recent years, while adiposis is increasingamong children and middle-aged and elderly persons, emaciationaccompanied with anorexia is increasing mainly among young women. Thus,failure of an eating-control mechanism has been widely recognized as apathological condition. In particular, anorexia nervosa has beenincreasing in number year by year, now becoming one of diseasesattracting even social attention. This disease is characterized by anextreme fall in the intake amount and uncontrollableness of maintaininga normal weight over the minimum due to the fall. Slightly more than 90%of the patients suffering from the disease are women, and the diseaseranks high in the adolescent female mortality rate. Because the diseaseis caused by an addition of a psychological trauma (pointing out offatness, etc.) or a stress to a problem in growth or a genetic factor,principal treatment means therefore depend much on hospitalized behaviortherapy.

[0003] For cancerous cachexia recognized in about 80% of patients dyingof cancer, appetite depression and emaciation, which are concomitantsymptoms, are the problems when considering a quality of life of apatient suffering from cancer, so that researches have been advancedregarding a mechanism of eating disorders and a treatment strategy moreintensively than ever. Although the cause of inappetence accompaniedwith suffering from cancer has not necessarily been elucidated yet,participation of various substances causing dysbolism (proinflammatorycytokines, neuroendocrine hormones, neurotransmitters, eicosanoids,tumor-derived factors, etc.) has been proposed, based on an idea that “asubstance causing cancerous cachexia being equal to a factor inducingappetite depression”. The prior treatment is mainly a forced energysupply by transfusion, while it is also known that the condition ofcancerous cachexia is not necessarily improved only by the treatment. Asrecent trends in treatment methods, there is an example in which use ofcorticosteroids and synthesized progesterons (megestorol acetate ormedroxyprogesteron acetate) is recommended to stimulate appetite of apatient suffering from cancer who is recognized as having appetitedepression or weight reduction. However, a guideline is still notclearly defined regarding how to use the above for obtaining the maximumeffect, analyses of results from future clinical trials are expected.Furthermore, agonists or antagonists of neuropeptides or drugs targetingTNF-α, IL-6, CRP, for example, are developed and are now in a stage ofclinical trial thereof [referential literature: Nihon Rinsho, Vol 59, No3, 515-520 (2001)]. Additionally, because combinational use ofanticancer drugs is widely adopted in chemotherapies of cancer, it isconsidered that there is a possibility of treatment with combinationaluse of existing anticancer drugs, in treatment of appetite depressionand emaciation accompanied with cancerous cachexia.

[0004] Under such circumstances as above, detailed elucidation of theeating-control mechanism is still being researched, and especially,clinical problems on anorexia and emaciation are not sufficientlysolved. Therefore, in addition to the treatment methods currently used,there is a strong desire for development of a further improved method ora novel treatment method.

[0005] JP 7-165708 A, JP 8-231505 A, and JP 2000-247949 A disclose thesame sulfonamide compounds and sulfonic acid ester compounds as thepresent invention, but there is no description about theappetite-stimulating effect thereof.

DISCLOSURE OF THE INVENTION

[0006] An object of the present invention is to provide anappetite-stimulating agent having an excellent appetite-stimulatingeffect. Another object of the present invention is to provide atherapeutic agent for anorexia based on an appetite-stimulating effect.

[0007] In view of the above, the inventors of the present invention havemade intensive studies for seeking an excellent appetite-stimulatingagent, and found that a sulfonamide compound and a sulfonic acid estercompound having a bicyclic hetero ring have an excellentappetite-stimulating effect and also have less toxicity, thus completingthe present invention.

[0008] The present invention provides an appetite-stimulating agentcomprising, as an active ingredient, a sulfonamide derivative orsulfonic acid ester derivative represented by the following generalformula (I):

[0009] wherein the ring A represents a monocyclic or bicyclic aromaticring which may be substituted,

[0010] the ring B represents a 6-membered unsaturated hydrocarbon ringor a 6-membered unsaturated heterocyclic ring containing one nitrogenatom as a heteroatom, each of which may be substituted,

[0011] the ring C represents a 5-membered heterocyclic ring containingone or two nitrogen atoms, which may be substituted,

[0012] W represents a single bond or —CH═CH—,

[0013] X represents —N(R¹)- or an oxygen atom,

[0014] Y represents a carbon atom or a nitrogen atom,

[0015] Z represents —N(R²)- or a nitrogen atom, and

[0016] R¹ and R² may be identical or different and each represents ahydrogen atom or a lower alkyl group, or a pharmacologically acceptablesalt thereof, or a hydrate thereof.

[0017] The present invention also provides a therapeutic agent foranorexia, comprising, as an active ingredient, a sulfonamide derivativeor sulfonic acid ester derivative represented by the above generalformula (I), or a pharmacologically acceptable salt thereof, or ahydrate thereof

[0018] In the general formula (I), it is preferred that W is a singlebond. More preferably, X and Z are —NH—, and Y is a carbon atom.

[0019] In the general formula (I), it is preferred that the ring B isbenzene or pyridine, each of which may be substituted.

[0020] In the general formula (I), it is preferred that the ring C ispyrrole which may be substituted.

[0021] In the general formula (I), it is preferred that the ring A isbenzene or pyridine, each of which may be substituted; the ring B isbenzene which may be substituted; the ring C is pyrrole which may besubstituted; W is a single bond; and X and Z are —NH—.

[0022] Examples of the anorexia include anorexia nervosa, apocleisisemaciation, and anorexia and emaciation accompanying cancerous cachexia.

[0023] When the anorexia is anorexia and emaciation accompanyingcancerous cachexia, it is preferred that the agent further comprises ananticancer drug.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIG. 1 shows an increase in the body weight of a mouse when thecompound used in the present invention is administered to the mouse.

[0025]FIG. 2 shows a change of the food consumption of a mouse when thecompound used in the present invention is administered to the mouse.

[0026]FIG. 3 shows an increase in the body weight of a mouse when thecompound of Compound 17 is administered to the mouse.

[0027]FIG. 4 shows a change of in the food consumption of a mouse whenthe compound of Compound 17 is administered to the mouse.

BEST MODE FOR CARRYING OUT THE INVENTION

[0028] In the general formula (I), the “monocyclic or bicyclic aromaticring which may be substituted” represented by the ring A is an aromatichydrocarbon ring or an aromatic heterocyclic ring containing at leastone of nitrogen, oxygen and sulfur atoms, each of which may have one tothree substituents thereon. Examples of such aromatic rings included inthe ring A include pyrrole, pyrazole, imidazole, thiophene, furan,thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine,naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, indole, isoindole, indolizine,indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole,benzopyrazole, benzothiazole and so forth. They may have one to threesubstituents. When two or more substituents are present, they may be thesame or different. Examples of the substituents include an amino groupwhich may be substituted with a lower alkyl gourp or a lower cycloalkylgroup; a lower alkyl group; a lower alkoxy group; hydroxyl; nitro;mercapto; cyano; a lower alkylthio group; a halogen group; a grouprepresented by the formula -a-b wherein a represents a single bond,—(CH₂)_(k)-, —O—(CH₂)_(k)-, —S—(CH₂)_(k)- or —N(R³)-(CH₂)_(k)-, k is aninteger of 1 to 5, R³ represents a hydrogen atom or a lower alkyl group,and b represents —CH₂-d (wherein d represents an amino group which maybe substituted with a lower alkyl group, a halogen group, hydroxyl, alower alkylthio group, cyano or a lower alkoxy group); a grouprepresented by the formula -a-e-f wherein a has the same meaning asdefined above, e represents —S(O)— or —S(O)₂-, f represents an aminogroup which may be substituted with a lower alkyl group or a loweralkoxy group, a lower alkyl group, trifluoromethyl, —(CH₂)_(m)-b or—N(R⁴)-(CH₂)_(m)-b (wherein b has the same meaning as defined above, R⁴represents a hydrogen atom or a lower alkyl group, and m is an integerof 1 to 5); a group represented by the formula -a-g-h wherein a has thesame meaning as defined above, g represents —C(O)— or —C(S)—, hrepresents an amino group which may be substituted with a lower alkylgroup, hydroxyl, a lower alkyl group, a lower alkoxy group, —(CH₂)_(n)-bor —N(R⁵)-(CH₂)_(n)-b (wherein b has the same meaning as defined above,R⁵ represents a hydrogen atom or a lower alkyl group, and n is aninteger of 1 to 5); a group represented by the formula -a—N(R⁶)-g-iwherein a and g have the same meanings as defined above, R⁶ represents ahydrogen atom or a lower alkyl group, i represents a hydrogen atom or alower alkoxy group or f (f has the same meaning as defined above); agroup represented by the formula -a—N(R⁷)-e-f wherein a, e and f havethe same meanings as defined above, and R⁷ represents a hydrogen atom ora lower alkyl group; a group represented by the formula—(CH₂)_(p)j-(CH₂)_(q)-b wherein j represents an oxygen atom or a sulfuratom, b has the same meaning as defined above, and p and q may be thesame or different and each represents an integer of 1 to 5; a grouprepresented by the formula —(CH₂)_(u)-Ar wherein Ar represents a phenylgroup or a heteraryl group, which may be substituted with a lower alkylgroup, a lower alkoxy group or a halogen atom and u represents 0 or aninterger of 1 to 5; a group represented by the formula—CONH—(CH₂)_(u)-Ar wherein Ar and u have the same meaning as definedabove; a group represented by the formula —SO₂-(CH₂)_(u)-Ar wherein Arand u have the same meaning as defined above; and so forth.

[0029] When the substituent is an amino group substituted with two ofalkyl groups, both of the alkyl groups may bond to form a 5- or6-membered ring. Further, when the ring A is a nitrogen-containingheterocyclic ring having hydroxyl or mercapto, these groups may presentin the form of an oxo or thioxo group by resonance.

[0030] The “6-membered unsaturated hydrocarbon ring or 6-memberedunsaturated heterocyclic ring containing one nitrogen atom as aheteroatom, which may be substituted” represented by the ring B meansbenzene or pyridine which may be partially hydrogenated. It may have oneor two of substituents on the ring, and when two of substituents arepresent, they may be the same or different.

[0031] The “5-membered heterocyclic ring containing one or two nitrogenatoms, which may be substituted” represented by the ring C meanspyrrole, pyrazole or imidazole which may be partially hydrogenated. Itmay have one or two of substituents on the ring, and when two ofsubstituents are present, they may be the same or different.

[0032] Examples of the substituents that the rings of B and C may haveinclude a halogen group, cyano, a lower alkyl group, a lower alkoxygroup, hydroxyl, oxo, a group represented by the formula —C(O)-r(wherein r represents a hydrogen atom, an amino group which may besubstituted with a lower alkyl group, a lower alkyl group, a loweralkoxy group or hydroxyl), an amino group substituted with a lower alkylgroup, trifluoromethyl and so forth.

[0033] In the general formula (I), the lower alkyl group in thedefinitions of R¹ and R² as well as the substituents that the rings ofA, B and C may have means a linear or branched alkyl group having 1 to 6carbon atoms, and examples thereof include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl),isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and so forth. Amongthese, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl arepreferred, and methyl, ethyl, n-propyl and isopropyl are most preferred.

[0034] The lower cycloalkyl group mentioned in the definitions of thesubstituents that the ring of A may have means a cycloalkyl group having3 to 8 carbon atoms, and examples thereof include cyclopropyl,cyclopentyl, cyclohexyl and so forth.

[0035] The lower alkoxy mentioned in the definitions of the substituentsthat the rings of A, B and C may have means an alkoxyl group derivedfrom the aforementioned lower alkyl group, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Among these,methoxy and ethoxy are most preferred. The lower alkylthio group meansan alkylthio group derived from the aforementioned lower alkyl group.Further, examples of the halogen atom include a fluorine atom, achlorine atom, a bromine atom and so forth.

[0036] The sulfonamide derivatives or the sulfonic acid esterderivatives represented by the general formula (I) may form a salt withan acid or a base. The active ingredient used in the present inventionalso includes salts of the sulfonamide derivatives or the sulfonic acidester represented by the general formula (I). Examples of the salt withan acid include salts with inorganic acids, such as hydrochlorides,hydrobromides and sulfates, and salts with organic acids such as aceticacid, lactic acid, succinic acid, fumaric acid, maleic acid, citricacid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid.Examples of the salt with a base include salts with inorganic bases,such as sodium salts, potassium salts and calcium salts and salts withorganic bases such as triethylamine, arginine and lysine.

[0037] It is needless to say that the compounds include hydrates andoptical isomers of these compounds if they are present.

[0038] A list of specific examples of the sulfonamide derivative or thesulfonic acid ester derivative represented by the general formula (I) orthe pharmacologically acceptable salt, or the hydrate thereof is asfollows:

[0039] Compound 1

[0040] N-(1H-Indol-7-yl)-4-nitrobenzenesulfonamide

[0041] Compound 2

[0042] N-(3-Chloro-1H-indol-7-yl)-4-nitrobenzenesulfonamide

[0043] Compound 3

[0044] 4-Amino-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide

[0045] Compound 4

[0046]N-(3-Chloro-1H-indol-7-yl)-4-(methanesulfonamido)-benzenesulfonamide

[0047] Compound 5

[0048] 4-Bromomethyl-N-(1H-indol-7-yl)benzenesulfonamide

[0049] Compound 6

[0050] N-(1,3-Dihydro-2H-indol-2-on-7-yl)-4-methyl-benzenesulfonamide

[0051] Compound 7

[0052] 3-Chloro-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide

[0053] Compound 8

[0054] 4-Amino-N-(3,4-dichloro-1H-indol-7-yl)benzenesulfonamide

[0055] Compound 9

[0056] 4-[N-(1H-Indol-7-yl)sulfamoyl]benzoic acid

[0057] Compound 10

[0058] N-(3-Chloro-1H-indol-7-yl)-4-cyanobenzenesulfonamide

[0059] Compound 11

[0060] 3-Chloro-N-(3-chloro-4-methoxy-1H-indol-7-yl)-benzenesulfonamide

[0061] Compound 12

[0062] 3-Chloro-N-(3-chloro-4-hydroxy-1H-indol-7-yl)-benzenesulfonamide

[0063] Compound 13

[0064] N-(1H-Indol-7-yl)-4-methoxybenzenesulfonamide

[0065] Compound 14

[0066] 6-Chloro-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide

[0067] Compound 15

[0068]N-(3-Chloro-1H-indol-7-yl)-4-(methylthiomethyl)-benzenesulfonamide

[0069] Compound 16

[0070] 3-Chloro-N-(3-formyl-1H-indol-7-yl)benzenesulfonamide

[0071] Compound 17

[0072] 3-Chloro-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide

[0073] Compound 18

[0074] 6-Chloro-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide

[0075] Compound 19

[0076] N-(3-Chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide

[0077] Compound 20

[0078] 3-Chloro-N-(8-imidazo[1,2-a]pyridinyl)benzenesulfonamidehydrochloride

[0079] Compound 21

[0080] N-(3,4-Dichloro-1H-indol-7-yl)-4-sulfamoyl-benzenesulfonamide

[0081] Compound 22

[0082] N-(3-Chloro-1H-indol-7-yl)-4-(methylthio)benzenesulfonamide

[0083] Compound 23

[0084] N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfonyl)-benzenesulfonamide

[0085] Compound 24

[0086] N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfinyl)-benzenesulfonamide

[0087] Compound 25

[0088]3-Chloro-N-(3-chloro-1H-pyrrolo[3,2-c]pyridin-7-yl)-benzenesulfonamide

[0089] Compound 26

[0090]4-Acetamido-N-(3-chloro-4-methyl-1H-indol-7-yl)-benzenesulfonamide

[0091] Compound 27

[0092] 4-Amino-N-(3-chloro-4-methyl-1H-indol-7-yl)-benzenesulfonamide

[0093] Compound 28

[0094] 4-Cyano-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide

[0095] Compound 29

[0096] 4-Carbamoyl-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide

[0097] Compound 30

[0098] N-(4-Bromo-1H-indol-7-yl)-4-nitrobenzenesulfonamide

[0099] Compound 31

[0100] N-(3-Chloro-4-cyano-1H-indol-7-yl)-4-nitro-benzenesulfonamide

[0101] Compound 32

[0102] 4-Amino-N-(3-chloro-4-cyano-1H-indol-7-yl)-benzenesulfonamide

[0103] Compound 33

[0104] 4-Amino-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide

[0105] Compound 34

[0106]N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfinylmethyl)-benzenesulfonamide

[0107] Compound 35

[0108]N-(3-Chloro-1H-indol-7-yl)-4-(2-sulfamoylethyl)-benzenesulfonamide

[0109] Compound 36

[0110]N-(3-Chloro-1H-indol-7-yl)-4-[2-(methylsulfonyl)ethyl]-benzenesulfonamide

[0111] Compound 37

[0112] 6-Amino-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide

[0113] Compound 38

[0114]4-Acetamide-3-chloro-N-(3-chloro-1H-indol-7-yl)-benzenesulfonamide

[0115] Compound 39

[0116] N-(3-Cyano-1H-indol-7-yl)-8-quinolinesulfonamide

[0117] Compound 40

[0118] 5-Chloro-N-(3-cyano-1H-indol-7-yl)-2-thiophenesulfonamide

[0119] Compound 41

[0120]N-(3-Chloro-1H-indol-7-yl)-4-(methoxycarbonylamino)-benzenesulfonamide

[0121] Compound 42

[0122] 4-Acetyl-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide

[0123] Compound 43

[0124]N-(3-Chloro-1H-indol-7-yl)-4-(N-methoxysulfamoyl)-benzenesulfonamide

[0125] Compound 44

[0126] N-(3-Cyano-1H-indol-7-yl)-p-styrenesulfonamide

[0127] Compound 45

[0128] 3-Chloro-N-(3-cyano-1H-indol-7-yl)-2-methyl-benzenesulfonamide

[0129] Compound 46

[0130] N-(3-Chloro-1H-indol-7-yl)-6-isopropylamino-3-pyridinesulfonamide

[0131] Compound 47

[0132]N-(3-Chloro-1H-indol-7-yl)-6-[[2-(dimethylamino)-ethyl]amino]-3-pyridinesulfonamide

[0133] Compound 48

[0134] N-(3-Cyano-1H-indol-7-yl)-2-furansulfonamide

[0135] Compound 49

[0136]N-(3-Chloro-1H-indol-7-yl)-4-[(dimethylaminosulfonyl)-amino]benzenesulfonamide

[0137] Compound 50

[0138] N-(3-Methyl-1H-indol-7-yl)-4-(methylsulfonyl)-benzenesulfonamide

[0139] Compound 51

[0140] 3-Cyano-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide

[0141] Compound 52

[0142]N-(3-Chloro-1H-indol-7-yl)-4-(N-methylmethanesulfonamido)-benzenesulfonamide

[0143] Compound 53

[0144]N-(3-Chloro-1H-indol-7-yl)-4-[(methanesulfonamido)methyl]-benzenesulfonamide

[0145] Compound 54

[0146]N-(3-Chloro-1H-indol-7-yl)-4-(1-pyrrolidinylsulfonyl)-benzenesulfonamide

[0147] Compound 55

[0148] N-(3-Cyano-1H-indol-7-yl)-1-methyl-4-imidazolesulfonamide

[0149] Compound 56

[0150]N-(3-Chloro-1H-indol-7-yl)-6-[(2-hydroxyethyl)amino]-3-pyridinesulfonamide

[0151] Compound 57

[0152] N-(3-Chloro-1H-indol-7-yl)-6-mercapto-3-pyridinesulfonamide

[0153] Compound 58

[0154]7-(4-Chlorobenzenesulfonamido)-1H-indole-2-carboxylic acid

[0155] Compound 59

[0156]N-(3-Chloro-1H-indol-7-yl)-6-cyclopropylamino-3-pyridinesulfonamide

[0157] Compound 60

[0158] N-(3-Cyano-1H-indol-7-yl)-5-methyl-3-pyridinesulfonamide

[0159] Compound 61

[0160]N-(3-Chloro-1H-indol-7-yl)-4-(N-methylsulfamoyl)-benzenesulfonamide

[0161] Compound 62

[0162]N-(3-Chloro-1H-indol-7-yl)-4-[2-(methanesulfonamido)ethyl]-benzensulfonamide

[0163] Compound 63

[0164] N-(3-Chloro-1H-indol-7-yl)-4-(sulfamoylmethyl)-benzensulfonamide

[0165] Compound 64

[0166] N-(3-Chloro-1H-indol-7-yl)-4-thiocarbamoylbenzensulfonamide

[0167] Compound 65

[0168] 5-Bromo-N-(3-cyano-1H-indol-7-yl)-2-pyridinesulfonamide

[0169] Compound 66

[0170] N-(3-Cyano-1H-indol-7-yl)-2-naphthalenesulfonamide

[0171] Compound 67

[0172] N-(3-Acetyl-1H-indol-7-yl)-3-chlorobenzenesulfonamide

[0173] Compound 68

[0174] 4-Amino-N-(5-bromo-3-cyano-1H-indol-7-yl)benzenesulfonamide

[0175] Compound 69

[0176]N-(3-Chloro-1H-indol-7-yl)-4-(N-ethylsulfamoyl)-benzenesulfonamide

[0177] Compound 70

[0178]N-(3-Chloro-1H-indol-7-yl)-4-(ethanesulfonamido)-benzenesulfonamide

[0179] Compound 71

[0180] N-(3-Chloro-1H-indol-7-yl)-6-[(2-cyanoethyl)amino]-3-pyridinesulfonamide

[0181] Compound 72

[0182]N-(3-Chloro-1H-indol-7-yl)-4-(N-methylcarbamoyl)-benzenesulfonamide

[0183] Compound 73

[0184]N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfonylmethyl)-benzenesulfonamide

[0185] Compound 74

[0186]N-(3-Chloro-1H-indol-7-yl)-4-(N,N-dimethylsulfamoyl)-benzenesulfonamide

[0187] Compound 75

[0188]N-(3-Chloro-1H-indol-7-yl)-4-(1-pyrrolidinylcarbonyl)-benzenesulfonamide

[0189] Compound 76

[0190] 3-Chloro-N-(3-chloro-1H-indol-7-yl)-N-methyl-benzenesulfonamide

[0191] Compound 77

[0192]N-(3,4-Dichloro-1H-indol-7-yl)-4-(sulfamoylmethyl)-benzenesulfonamide

[0193] Compound 78

[0194]N-(3-Cyano-1H-indol-7-yl)-4-[2-(methylsulfonyl)ethyl]-benzenesulfonamide

[0195] Compound 79

[0196]N-(3-Chloro-1H-indol-7-yl)-4-(N-methylacetamido)-benzenesulfonamide

[0197] Compound 80

[0198] N-(3-Chloro-1H-indol-7-yl)-6-hydroxy-3-pyridinesulfonamide

[0199] Compound 81

[0200] N-(3-Chloro-1H-indol-7-yl)-4-[2-(N-methylmethane-sulfonamido)ethyl]benzenesulfonamide

[0201] Compound 82

[0202]N-(3-Chloro-1H-indol-7-yl)-4-(trifluoromethane-sulfonamido)benzenesulfonamide

[0203] Compound 83

[0204]N-(3-Chloro-1H-indol-7-yl)-4-[(N-methylmethane-sulfonamido)methyl]benzenesulfonamide

[0205] Compound 84

[0206]3-Chloro-N-(3-chloro-1H-pyrrolo[2,3-c]pyridin-7-yl)-benzenesulfonamide

[0207] Compound 85

[0208] 4-(3-Bromopropyl)-N-(3-chloro-1H-indol-7-yl)- benzenesulfonamide

[0209] Compound 86

[0210]4-[N-(2-Bromoethyl)sulfamoyl]-N-(3-chloro-1H-indol-7-yl)-benzenesulfonamide

[0211] Compound 87

[0212]N-(3-Chloro-1H-indol-7-yl)-4-[3-(1-imidazolyl)propyl]-benzenesulfonamide

[0213] Compound 88

[0214]N-(3-Chloro-1H-indol-7-yl)-4-[N-(2-(2-pyridinyl)ethyl)-carbamoyl]benzenesulfonamide

[0215] Compound 89

[0216] 4-Amidino-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide

[0217] Compound 90

[0218]N-(3-Chloro-1H-indol-7-yl)-4-[N-[2-(1-imidazolyl)ethyl]-sulfamoyl]benzenesulfonamide

[0219] Compound 91

[0220]3-(5-Bromonicotinamido)-N-(3-cyano-1H-indol-7-yl)-benzenesulfonamide

[0221] Compound 92

[0222] N-(3-Chloro-1H-indol-7-yl)-4-[N-(2-thiazolyl)sulfamoyl]-benzenesulfonamide

[0223] Compound 93

[0224] 5-Chloro-N-(3-chloro-1H-indol-7-yl)-4-(5-methyl-3-pyridinesulfonamido)-2-thiophenesulfonamide

[0225] Compound 94

[0226] 3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)-benzenesulfonamide

[0227] The sulfonamide derivative or the sulfonic acid ester derivativerepresented by the general formula (I), a pharmacologically acceptablesalt thereof, or a hydrate of the same (hereinafter, also referred as“the compound represented by the general formula (I)”) may bemanufactured by various methods. Among them, representative methods aredescribed in JP 07-165708 A, JP 08-231505 A, and JP 2000-247949 A.

[0228] The compound represented by the general formula (I) has anexcellent appetite-stimulating effect. Thus, the compound represented bythe general formula (I) may be used as an active ingredient for anappetite-stimulating agent. It may also be used as an active ingredientof a therapeutic agent for diseases in which appetite stimulation iseffective to treatment thereof. Thus, according to the presentinvention, there is provided a method for stimulating appetite,comprising administering an effective amount of the compound representedby the general formula (I); and a method for treating a disease in whichappetite stimulation is effective to treatment thereof, comprisingadministering an effective amount of the compound represented by thegeneral formula (I). Also, according to the present invention, there isprovided a use of the compound represented by the general formula (I) inmanufacture of an appetite-stimulating agent, and a use of the compoundrepresented by the general formula (I) in manufacture of a therapeuticagent for a disease in which appetite stimulation is effective totreatment thereof.

[0229] The phrase “the compound represented by the general formula (I)as an active ingredient” includes a compound that generates the compoundrepresented by the general formula (I) due to in vivo metabolism such asoxidation, reduction, and hydrolysis.

[0230] Similarly, the phrases “administering the compound represented bythe general formula (I)” and “use of the compound represented by thegeneral formula (I)” in the present invention also include administeringand using a compound which generates the compound represented by thegeneral formula (I) due to in vivo metabolism such as oxidation,reduction, and hydrolysis, respectively.

[0231] In the present invention, the word “treatment” also includesalleviating a symptom of a disease.

[0232] Examples of the disease in which appetite stimulation iseffective to treatment thereof include anorexias. Examples of theanorexias include anorexia nervosa, apocleisis emaciation, anorexia andemaciation accompanying cancerous cachexia, etc.

[0233] The compound represented by the general formula (I) may be usedin a preparation made by a general method. For example, it may be acomposition with a carrier (if used for a medicine, a pharmacologicallyacceptable carrier).

[0234] The compound represented by the general formula (I), if used as amedicine, is administered orally or parenterally. The dose is differentdepending on degree of a symptom, age of a patient, sex, body weight,sensibility difference, administration method, administration timing,administration interval, medicinal characteristics, preparation,allegation, type, type of active ingredient, or the like. The dose isgenerally 10 to 6,000 mg, preferably about 50 to 4,000 mg, morepreferably 100 to 3,000 mg per day for an adult, which was separatelyadministered generally 1 to 3 time(s) in a day, but there is noparticular limitation thereto.

[0235] In order to prepare an oral solid dosage form, a vehicle andoptionally with a binder, disintegrator, lubricant, colorant,corrective, etc. are added to a base, and a mixture thereof is thentreated in accordance with a conventional method to form tablets, coatedtablets, granules, fine granules, powder, capsules, etc.

[0236] Examples of the vehicle include lactose, cornstarch, saccharose,glucose, sorbitol, crystalline cellulose, and silicon dioxide. Examplesof the binder include polyvinyl alcohol, ethylcellulose,methylcellulose, acacia gum, hydroxypropylcellulose, andhydroxypropylmethylcellulose. Examples of the lubricant includemagnesium stearate, talc, and silica. As the colorant, one permitted toadd to a drug is used. Examples of the corrective include cocoa powder,menthol, aromatic acid, peppermint oil, borneol, and cinnamon powder. Asa matter of course, those tablets and granules may optionally be coatedappropriately with sugar, gelatin, etc.

[0237] In order to prepare an injection, a pH regulator, a buffer, asuspending agent, a solubilizer, a stabilizer, an isotonizing agent, apreservative, etc. are optionally added to a base, and a mixture thereofis then treated in accordance with a conventional method to form aninjection for intravenous, hypodermic, or intramuscular injection. Theinjection may optionally be treated in accordance with a conventionalmethod to form a freeze-dry product.

[0238] Examples of the suspending agent include methylcellulose,polysorbate 80, hydroxyethylcellulose, acacia gum, tragacanth powder,sodium carboxymethylcellulose, and polyoxyethylenesorbitan monolaurate.

[0239] Examples of the solubilizing agent include polyoxyethylenehardened castor oil, polysorbate 80, nicotinic acid amide,polyoxyethylenesorbitan monolaurate, macrogol, and castor oil fatty acidethyl ester.

[0240] Examples of the stabilizer include sodium sulfite and sodiummetasulfite. Examples of the preservative include methylparaoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, andchlorocresol.

[0241] If the anorexia is anorexia and emaciation accompanying cancerouscachexia, the therapeutic agent for anorexia is preferred to furtherinclude an anticancer drug.

[0242] Examples of the anticancer drug include 5-fluorouracil,cisplatin, irinotecan hydrochloride, paclitaxel, epirubicin, etc.

[0243] The compound represented by the general formula (I) and theanticancer drug may be mixed or separately encased to be packed in aunit.

[0244] The compound represented by the general formula (I) and theanticancer drug may be administered simultaneously or in order.

EXAMPLES

[0245] The effect of the compounds used in the present invention willnow be described with reference to pharmacological experimentalexamples.

[0246] Pharmacological experimental example 1: Appetite-stimulating andbody weight-increasing effects

[0247] A subjective compound was suspended in saline containing 3.5%dimethylsulfoxide and 6.5% Tween 80, and intraperitoneally administeredto BDF₁ mice (7 weeks old, female) in a given amount once a day for 15days (day 0 to day 14). To mice of a control group, saline containing3.5% dimethylsulfoxide and 6.5% Tween 80 was intraperitoneallyadministered. Administration was conducted at 1 p.m. every day, and thebody weight (day 0 to day 15) and the food intake since the precedingday (day 1 to day 15) were weighed immediately before theadministration. The experiments were conducted using 5 mice per groupfor each of the drug-administered group and the control group.Experimental results for the Compounds 10, 17, 51, and 94 are shown inFIGS. 1 and 2. The numbers of the compound examples are the same as inthe list described above (hereinafter, the same applies). As is apparentfrom the experimental results, it was found that administration of thecompounds of the Compounds 10, 17, 51, and 94 increased the body weightand food intake.

[0248] Pharmacological experimental example 2: Gene expression analysisof white adipose tissues by GeneChip (Affymetrix)

[0249] The compound of the Compound 17 was suspended in salinecontaining 3.5% dimethylsulfoxide and 6.5% Tween 80, andintraperitoneally administered to BDF₁ mice (7 weeks old, female) in anamount of 200 mg/kg once a day for 15 days (day 0 to day 14). To mice ofa control group, saline containing 3.5% dimethylsulfoxide and 6.5% Tween80 was intraperitoneally administered. The experiments were conductedusing 5 mice per group for each of the drug-administered group and thecontrol group. On day 15, white adipose tissues were collected from themice of the drug-administered group and the control group, and wereexamined for expression levels of mRNA using GeneChip (Affymetrix)Murine Genome U74A. The experimental operation was conducted inaccordance with GeneChip Expression Analysis Technical Manual, and thequantitative analysis was conducted using GeneChip Software. FIG. 3shows changes in body weights and food intakes of the mice of thedrug-administered group and the control group during the experimentalperiod. The comparison results of gene expression patterns of thedrug-administered group and the control group elucidated that mRNAlevels of a plurality of gene products, which are reported as factorsparticipating in appetite repression or mediators of cancerous cachexia,were significantly repressed. Results regarding representative genes aresummarized in Table 1. TABLE 1 Expression level ratio (drug-administeredgroup/ Accession # Gene name control group) X54542 Interleukin-6 24%M15131 Interleukin-1-beta 22% M88242 griPGHS* 26%

[0250] As is apparent from the above experimental examples, the compoundrepresented by the general formula (I) has an excellentappetite-stimulating effect. Therefore, the compound is useful, as atherapeutic agent for anorexia, in treatment for diseases such asanorexia nervosa, apocleisis emaciation, and anorexia and emaciationaccompanying cancerous cachexia.

[0251] When the compounds of the Compounds 10, 17, 51, and 94 wereadministered to mice in a dose of 100 mg/kg and 200 mg/kg successivelyfor 15 days, the mice were in a quite normal condition, with a bodyweight increase depending on dose, and there was no observationindicating toxicity. Thus, it is considered that the compoundrepresented by the general formula (I) has low toxicity.

INDUSTRIAL APPLICABILITY

[0252] An appetite-stimulating agent and a therapeutic agent foranorexia are provided.

1. A composition comprising, a carrier and and appetite-simulating agentas an active ingredient, wherein the appetite-stimulating agent is asulfonamide derivative or sulfonic acid ester derivative represented byformula (I):

or a pharmacologically acceptable salt thereof or a hydrate thereof,wherein ring A represents a monocyclic or bicyclic aromatic ring whichis optionally substituted, ring B represents a 6-membered unsaturatedhydrocarbon ring or a 6-membered unsaturated heterocyclic ringcontaining one nitrogen atom as a heteroatom, wherein the hydrocarbonring or the heterocyclic ring is optionally substituted, ring Crepresents a 5-membered heterocyclic ring containing one or two nitrogenatoms, wherein ring C is optionally substituted, W represents a singlebond or —CH═CH—, X represents —N(R¹)- or an oxygen atom, Y represents acarbon atom or a nitrogen atom, Z represents —N(R²)- or a nitrogen atom,and R¹ and R² may be identical or different and each represents ahydrogen atom or a lower alkyl group.
 2. The composition according toclaim 1, wherein W is a single bond.
 3. The composition according toclaim 2, wherein X and Z are —NH—, and Y is a carbon atom.
 4. Theappetite stimulating agent composition according to any one claim 1,wherein ring B is benzene or pyridine, each of which may be wherein thebenzene or the pyridine is optionally substituted.
 5. The compositionaccording to claim 1, wherein the ring C is pyrrole which is optionallysubstituted.
 6. The composition according to claim 1, wherein ring A isbenzene or pyridine, wherein the benzene or the pyridine is optionallysubstituted; ring B is benzene which is optionally substituted; ring Cis pyrrole which is optionally substituted; W is a single bond; and Xand Z are —NH—.
 7. A method of treating anorexia, comprising,administering to a mammal a sulfonamide derivative or sulfonic acidester derivative represented by formula (I):

or a pharmacologically acceptable salt thereof or a hydrate thereofwherein ring A represents a monocyclic or bicyclic aromatic ring whichis optionally substituted, ring B represents a 6-membered unsaturatedhydrocarbon ring or a 6-membered unsaturated heterocyclic ringcontaining one nitrogen atom as a heteroatom, wherein the hydrocarbonring or the heterocyclic ring is optionally substituted, ring Crepresents a 5-membered heterocyclic ring containing one or two nitrogenatoms, wherein ring C is optionally substituted, W represents a singlebond or —CH═CH—, X represents —N(R¹)- or an oxygen atom, Y represents acarbon atom or a nitrogen atom, Z represents —N(R²)- or a nitrogen atom,and R¹ and R² may be identical or different and each represents ahydrogen atom or a lower alkyl group.
 8. The method according to claim7, wherein W is a single bond.
 9. The method according to claim 8,wherein X and Z are —NH—, and Y is a carbon atom.
 10. The therapeuticagent method according to claim 7, wherein ring B is benzene orpyridine, wherein the benzene or the pyridine is optionally substituted.11. The method according to claim 7, wherein ring C is pyrrole which isoptionally substituted.
 12. The method according to claim 7, whereinring A is benzene or pyridine, wherein the benzene or the pyridine isoptionally substituted; ring B is benzene which is optionallysubstituted; ring C is pyrrole which is optionally substituted; W is asingle bond; and X and Z are —NH—.
 13. The method according to claim 7,wherein the anorexia is a disease selected from the group consisting ofanorexia nervosa, apocleisis emaciation, and anorexia and emaciationaccompanying cancerous cachexia.
 14. The method according to claim 13,wherein the anorexia is anorexia and emaciation accompanying cancerouscachexia, and the method further comprises administering to the mammalan anticancer drug.